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Cognitive and cortical plasticity deficits correlate with altered amyloid-? CSF levels in multiple sclerosis.

ABSTRACT: Cognitive dysfunction is of frequent observation in multiple sclerosis (MS). It is associated with gray matter pathology, brain atrophy, and altered connectivity, and recent evidence showed that acute inflammation can exacerbate mental deficits independently of the primary functional system involved. In this study, we measured cerebrospinal fluid (CSF) levels of amyloid-?(1-42) and ? protein in MS and in clinically isolated syndrome patients, as both proteins have been associated with cognitive decline in Alzheimer's disease (AD). In AD, amyloid-?(1-42) accumulates in the brain as insoluble extracellular plaques, possibly explaining why soluble amyloid-?(1-42) is reduced in the CSF of these patients. In our sample of MS patients, amyloid-?(1-42) levels were significantly lower in patients cognitively impaired (CI) and were inversely correlated with the number of Gadolinium-enhancing (Gd+) lesions at the magnetic resonance imaging (MRI). Positive correlations between amyloid-?(1-42) levels and measures of attention and concentration were also found. Furthermore, abnormal neuroplasticity of the cerebral cortex, explored with ? burst stimulation (TBS), was observed in CI patients, and a positive correlation was found between amyloid-?(1-42) CSF contents and the magnitude of long-term potentiation-like effects induced by TBS. No correlation was conversely found between ? protein concentrations and MRI findings, cognitive parameters, and TBS effects in these patients. Together, our results indicate that in MS, central inflammation is able to alter amyloid-? metabolism by reducing its concentration in the CSF and leading to impairment of synaptic plasticity and cognitive function.

SUBMITTER: Mori F

PROVIDER: S-EPMC3055691 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Cognitive and cortical plasticity deficits correlate with altered amyloid-β CSF levels in multiple sclerosis.

Mori Francesco F Rossi Silvia S Sancesario Giulia G Codecà Claudia C Mataluni Giorgia G Monteleone Fabrizia F Buttari Fabio F Kusayanagi Hajime H Castelli Maura M Motta Caterina C Studer Valeria V Bernardi Giorgio G Koch Giacomo G Bernardini Sergio S Centonze Diego D

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20101013 3

Cognitive dysfunction is of frequent observation in multiple sclerosis (MS). It is associated with gray matter pathology, brain atrophy, and altered connectivity, and recent evidence showed that acute inflammation can exacerbate mental deficits independently of the primary functional system involved. In this study, we measured cerebrospinal fluid (CSF) levels of amyloid-β(1-42) and τ protein in MS and in clinically isolated syndrome patients, as both proteins have been associated with cognitive ...[more]

PMID: 20944553

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Project description:Introduction and methodsIn order to verify whether parvalbumin (PVALB), a protein specifically expressed by GABAergic interneurons, could be a MS-specific marker of grey matter neurodegeneration, we performed neuropathology/molecular analysis of PVALB expression in motor cortex of 40 post-mortem progressive MS cases, with/without meningeal inflammation, and 10 control cases, in combination with cerebrospinal fluid (CSF) assessment. Analysis of CSF PVALB and neurofilaments (Nf-L) levels combined with physical/cognitive/3TMRI assessment was performed in 110 naïve MS patients and in 32 controls at time of diagnosis.ResultsPVALB gene expression was downregulated in MS (fold change = 3.7 ± 1.2, P < 0.001 compared to controls) reflecting the significant reduction of PVALB+ cell density in cortical lesions, to a greater extent in MS patients with high meningeal inflammation (51.8, P < 0.001). Likewise, post-mortem CSF-PVALB levels were higher in MS compared to controls (fold change = 196 ± 36, P < 0.001) and correlated with decreased PVALB+ cell density (r = -0.64, P < 0.001) and increased MHC-II+ microglia density (r = 0.74, P < 0.01), as well as with early age of onset (r = -0.69, P < 0.05), shorter time to wheelchair (r = -0.49, P < 0.05) and early age of death (r = -0.65, P < 0.01). Increased CSF-PVALB levels were detected in MS patients at diagnosis compared to controls (P = 0.002). Significant correlation was found between CSF-PVALB levels and cortical lesion number on MRI (R = 0.28, P = 0.006) and global cortical thickness (R = -0.46, P < 0.001), better than Nf-L levels. CSF-PVALB levels increased in MS patients with severe cognitive impairment (mean ± SEM:25.2 ± 7.5 ng/mL) compared to both cognitively normal (10.9 ± 2.4, P = 0.049) and mild cognitive impaired (10.1 ± 2.9, P = 0.024) patients.ConclusionsCSF-PVALB levels reflect loss of cortical interneurons in MS patients with more severe disease course and might represent an early, new MS-specific biomarker of cortical neurodegeneration, atrophy, and cognitive decline.

Dataset Information

Cognitive and cortical plasticity deficits correlate with altered amyloid-? CSF levels in multiple sclerosis.

Publications

Cognitive and cortical plasticity deficits correlate with altered amyloid-β CSF levels in multiple sclerosis.

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